Accelerometer-derived sleep metrics in mild and difficult-to-treat asthma

Introduction Poor sleep health is associated with increased asthma morbidity and mortality. Accelerometers have been validated to assess sleep parameters though studies using this method in patients with asthma are sparse and none have compared mild to difficult-to-treat asthma populations. Methods We performed a retrospective analysis from two recent in-house trials comparing sleep metrics between patients with mild and difficult-to-treat asthma. Participants wore accelerometers for 24-hours/day for seven days. Results Of 124 participants (44 mild, 80 difficult-to-treat), no between-group differences were observed in sleep-window, sleep-time, sleep efficiency or wake time. Sleep-onset time was ~ 40 min later in the difficult-to-treat group (p = 0.019). Discussion Broadly, we observed no difference in accelerometer-derived sleep-metrics between mild and difficult-to-treat asthma. This is the largest analysis of accelerometer-derived sleep parameters in asthma and the first comparing groups by asthma severity. Sleep-onset initiation may be delayed in difficult-to-treat asthma but a dedicated study is needed to confirm.


Introduction
Uncontrolled asthma can affect sleep quality as increased nocturnal symptoms are synonymous with uncontrolled disease.However, short or excessive sleep duration and poor sleep quality are risk factors for asthma exacerbations and healthcare usage, poorer quality of life and Allergy, Asthma & Clinical Immunology performed a cross-sectional, proof-of-concept analysis comparing sleep parameters from participants with mild and difficult-to-treat asthma utilising accelerometer technology.

Materials and methods
Data for this analysis was retrieved from two recent local trials approved by the West of Scotland Regional Ethics Committee (references 16/WS/0200 and 18/WS/0216) and undertaken between 2017 and 2021: one of pulmonary rehabilitation in difficult-to-treat asthma associated with raised body mass index (BMI) alongside a sub-study of activity levels in mild asthma, and a second trial studying weight loss in difficult-to-treat asthma and obesity (trial identifiers: NCT03630432, NCT03858608).Full trial protocols are described elsewhere [3,4].Both trials were funded by an NHS Greater Glasgow and Clyde Endowment Fund, and none of the contributors to the fund had any input in trial design, results or interpretation, nor any input into this retrospective analysis.All participants provided written consent for data use in future studies.Briefly, difficult-to-treat asthma was defined as per SIGN/BTS and GINA guidelines [5,6], including presence of characteristic symptoms, reversibility (≥ 12% and 200mls increase in FEV 1 post-bronchodilator) or bronchial hyper-reactivity on bronchial challenge testing; asthma treatment with high-dose inhaled corticosteroid (ICS); poor asthma control (Asthma Control Questionnaire score > 1.5) or ≥ 2 exacerbations requiring oral corticosteroids (OCS) or ≥ 1 asthma exacerbation requiring hospitalisation in the preceding 12 months.Patients with mild active asthma (asthma treatment within the preceding 12 months) were recruited from primary care.Mild disease was categorised by maximum preventer treatment with moderate-dose ICS/long-acting β-agonist combination, ACQ ≤ 1.5, < 2 exacerbations requiring OCS treatment and no hospital admissions with asthma in the preceding 12 months.
As part of the trial assessments, participants wore an ActiGraph wGT3X-BT accelerometer (ActiGraph, Pensacola, USA) on their non-dominant wrist continually for 7 days (excluding bathing).Devices were initialised to capture data at 30 Hz. Raw data was downloaded using ActiLife software (v.6.14.3;ActiGraph) and saved as .gt3xfiles and converted to .csvfiles.Data was exported into R v4.1.2(R Foundation for Statistical Computing, Vienna, Austria) for subsequent processing using the GGIR package (v2.6.0).
Among the variables extracted were number of nights devices were worn; mean sleep window time (time from initial sleep-onset to waking); mean sleep time (accumulated sustained inactivity sojourns overnight); sleep efficiency (sleep time: sleep window); sleep-onset time and wake time.Time variables were described as hours and minutes or 24-hour clock where appropriate.Variables were non-parametric and so summarised as median (IQR) and compared between mild and difficult-to-treat asthma groups using the Mann-Whitney U test.Data was analysed using IBM SPSS Statistics (version 28.0) and significance was set at 0.05.

Results
Of 133-patient data-sets available, nine were excluded due to lack of data (defined ≤ 3 nights use), leaving 124 participants (44 with mild asthma, 80 with difficult-totreat asthma).Of the 124, 56% were female, median (IQR) age was 57 (47, 64) years and the majority were never and ex-smokers (56% and 38% respectively).Baseline characteristics (Table 1) showed differences between mild and difficult-to-treat participants in atopy, weight, BMI, asthma control and quality of life, long-acting β-agonist (LABA) use and number of annual exacerbations.Higher baseline fractional exhaled nitric oxide (FeNO) and peripheral eosinophils were observed in the difficult-totreat asthma group compared to mild asthma.
No differences were observed in sleep time, sleep window, sleep efficiency or wake time between the mild and difficult-to-treat groups, though sleep-onset time was later in the difficult-to-treat asthma group (00:24; 23:16, 02:02) compared to mild asthma (23:41; 22:52, 00:45; p = 0.019).In the overall dataset (I.e., mild and difficultto-treat groups together), Spearman's rank showed no correlation between sleep-onset time and ACQ (marker of asthma control); rho = 0.049, p = 0.589.Additionally, both unadjusted and adjusted (correcting for weight) linear regression using sleep-onset time as the dependent variable and ACQ as the independent variable showed no relationship between asthma control and sleep-onset time: unadjusted F(1,122) = 0.28, p = 0.866; adjusted for weight F(2,121) = 0.160, p = 0.852.

Discussion
We observed no differences in sleep duration or efficiency between mild and difficult-to-treat groups, but whilst there was no difference in wake time, there was a later time of sleep-onset in the difficult-to-treat group which may reflect greater difficulty in sleep initiation in this cohort.The clinical significance of this difference (~ 40 min) is uncertain, however, interestingly correlation and regression analysis suggest this difference is not related to asthma control even when adjusted for weight, a key factor in sleep health.There was a significant between-group difference in proportion of participants with regular LABA use and it is feasible that β-agonistmediated stimulation could be related to the delay in sleep initiation in the difficult-to-treat group.Compared to the recommended sleep duration, patients from our cohort appear to be on the lower side (6.59 h; 5.04, 7.75) suggesting poorer sleep health despite good sleep efficiency.Factors associated with delayed sleep initiation and reduced sleep duration in difficult-to-treat asthma therefore remain to be elucidated and require further study.
Our results are similar to a study performed in 56 healthy adults (mean age 24.5 ± 4.5 years) also using Acti-Graph devices (non-dominant wrist) without sleep logs that showed (mean ± SD) sleep time (6 h 56 min ± 49 min), sleep window (7 h 59 min ± 51 min) and sleep efficiency (87%±4), as well as similar sleep-onset (00:05 ± 90 min) and wake times (08:20 ± 84 min) [7].A small study of 10 patients with mild-to-moderate asthma [2] showed reduced sleep time of 5 h 54 min ± 74 min with a similar mean sleep window time of 7 h 34 min ± 40 min.However, this study is clearly limited by the small sample size.
Our retrospective analysis has potential limitations.Firstly, groups were not equally weighted with more patients with difficult-to-treat asthma than mild asthma.Secondly, the initial trials data did not include objective assessments of daytime or nocturnal sleep (e.g., Epworth sleep score, Pittsburgh sleep quality index), nor any sleep logs.Thirdly, this analysis was not powered to assess sleep outcomes.Finally, this analysis did not account for factors such as sleep-disordered breathing that may influence outcomes, which should be addressed in future studies.Despite this, key strengths of our study  are the sample size, higher than in previous studies, and observed excellent tolerance of accelerometer use (93%).
To our knowledge this is the first comparison of mild and difficult-to-treat asthma sleep outcomes using accelerometery and we highlight a difference in sleep initiation between groups unrelated to asthma control and weight.
Further study is warranted to explore the relationship between asthma severity and sleep-metrics and whether interventions targeting sleep health can improve asthma outcomes.
In summary, patients with difficult-to-treat asthma may have delayed initiation of sleep compared to mild asthma, though this observation appears to be independent of asthma control and obesity.Other sleep parameters are broadly comparable to the general population.Accelerometers are well tolerated, offer more pragmatism than polysomnography and can be used to assess sleep outcomes in asthma but dedicated trials are needed before any definitive conclusions can be drawn.

Table 2
Sleep parameters of asthma patients overall and by disease severity Variables described as median (IQR) in hours:mins unless specified.*Mann Whitney U test comparing mild vs. difficult-to-treat asthma groups